PROJECT SUMMARY/ABSTRACT A paradigm shift in recent years has given rise to the field of systems/network pharmacology whose focus is identifying drug candidates that act via modulation of multiple networked targets. It is likely that drugs that can simultaneously inhibit multiple network targets within a specific pathway will exhibit greater efficacy than those that target a single cellular target. Moreover, cancer is a result of numerous genetic and molecular changes, systems/network pharmacology has the opportunity to identify the key nodes and allow the development of dual pathway targeting drugs. Hence, developing dual targeting small molecule therapeutic drugs that can selectively trigger cancer cell death via two distinct pathway targeting mechanisms is exceedingly attractive. Specifically, we expect that drugs that can elicit 1) oxidative damage and 2) endogenous prevention in a synergistic fashion will result in enhanced selectivity and efficacy since normal cells are believed to have a greater capacity for reactive oxygen species (ROS) adaptation. The goals of this proposal are 1) fine-tuning redox potentials of ferrocenylated gold(I) complexes to increase cellular uptake with increased ROS production, and 2) tuning gold-carbene bond strength to enhance intra cellular drug stability. This proposed research is predicated upon strong preliminary data showing that probes of this design [(Fc-NHC)2Au]+ (NHC = N-heterocyclic carbene, Fc = ferrocene) target cellular antioxidant pathways through modulation of oxidative stress and inhibition of thioredoxin reductase in lung cancer cell models. To accomplish these goals, we propose to chemically tune the reduction potential of various gold(I) complexes ([(RnFc-NHC)2Au]+; n = 1/2/5) featuring alkylated-ferrocenes to systematically evaluate the Structure Activity Relationship (SAR) as an effect of redox potentials of ferrocene. In conjunction, ([(NHC)2Au]+ complexes featuring varying Au-Ccarbene bond strength will be targeted to systematically evaluate extracellular stability in combination with intracellular Au release. At the completion of these aims, we hope to have developed a series of therapeutic drugs that elicit higher level of cancer specific ROS with increased cellular uptake and display greater intracellular stability to minimize side effects that are exhibited by current chemotherapy drugs. Given the cross-disciplinary nature of this work 5-7 undergraduates, 2 master's and 1 doctoral student will be exposed to a dynamic and critical area of biomedical research.